3-substituted and optionally 1-substituted azacyclic or azabicyclic compounds, pharmaceutical compositions, thereof and their use as stimulants of cognitive functions

ABSTRACT

Azacyclic compounds selected from the group consisting of ##STR1## wherein R 1  is H or C 1-6  -alkyl 
     R 3  is ##STR2## wherein R&#39; is C 3-8  -alkyl, cyclopropyl, C 4-8  -cycloalkyl, benzyl which may be substituted, or C 1-4  -alkoxy-C 1-4  -alkyl, and 
     R&#34; is H or C 1-8  -alkyl or C 1-6  -alkoxy or C 1-4  -alkoxy-C 1-4  -alkyl or aryl, and 
     R&#39;&#34; is H or C 1-6  -alkyl or C 4-8  -cycloalkyl; and 
     R 4  is H, C 1-8  -alkyl or Cl; and ##STR3##  provided that R 3  is not ##STR4##  wherein R&#39; is C 3-8  -alkyl, cyclopropyl or C 1-3  -alkoxymethyl, and provided that R 3  is not --CH═N--OR&#39;&#34;, wherein R&#39;&#34; is H or C 1-6  -alkyl, when the compounds of formula I is ##STR5##  and a salt thereof with a pharmaceutically-acceptable acid. The new compounds are useful in improving the cognitive functions of the forebrain and hippocampus of mammals, and are useful in the treatment of Alzheimer&#39;s disease.

The present invention relates to therapeutically active azacycliccompounds, a method of preparing the same and to pharmaceuticalcompositions comprising the compounds. The novel compounds are useful asstimulants of the cognitive function of the forebrain and hippocampus ofmammals and especially in the treatment of Alzheimer's disease.

Due to the in general improved health situation in the western world,elderly-related diseases are much more common now than in the past andare likely to be even more common in the future.

One of the elderly-related symptoms is a reduction of the cognitivefunctions. This symptom is especially pronounced in thepatophysiological disease known as Alzheimer's disease. This disease iscombined with, and also most likely caused by, a up to 90% degenerationof the muscarinic cholinergic neurons in nucleus basalis, which is partof substantia innominata. These neurons project to the prefrontal cortexand hippocampus and have a general stimulatory effect on the cognitivefunctions of the forebrain as well as of hippocampus , namely learning,association, consolidation, and recognition.

It is a characteristic of Alzheimer's disease that although thecholinergic neurons degenerate, then the postsynaptic muscarinicreceptors in the forebrain and hippocampus still exist. Thereforemuscarinic cholinergic agonists are useful in the treatment ofAlzheimer's disease and in improving the cognitive functions of elderlypeople.

It is well known that arecoline (methyl1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate) is such a cholinergicagonist.

Arecoline however has a very short biological half life and a smallseparation between central and peripheral muscarinic effects.Furthermore arecoline is a rather toxic compound.

Accordingly it is an object of the invention to provide new muscariniccholinergic compounds.

The novel compounds of the invention of formula I are heterocycliccompounds selected from the group consisting of: ##STR6## wherein

R¹ is H or C₁₋₆ -alkyl

R³ is ##STR7## R³ is C₃₋₈ -alkyl, cyclopropyl, C₄₋₈ -cycloalkyl, benzylwhich may be substituted or C₁₋₄ -alkoxy-C₁₋₄ -alkyl, and

R" is H or C₁₋₈ -alkyl or C₁₋₆ -alkoxy or C₁₋₄ -alkoxy-C₁₋₄ -alkyl oraryl, and

R'" is H or C₁₋₆ -alkyl or C₄₋₈ -cycloalkyl; and

R⁴ is H, C₁₋₈ -alkyl or Cl; ##STR8## provided that R³ is not ##STR9##wherein R' is C₃₋₈ -alkyl, cyclopropyl or C₁₋₃ -alkoxymethyl, andprovided that R³ is not --CH═N--OR'", wherein R'" is H or C₁₋₆ -alkyl,when the compounds of formula I is ##STR10## and a salt thereof with apharmaceutically-acceptable acid.

Examples of such salts include inorganic and organic acid addition saltssuch as hydrochloride, hydrobromide, sulphate, phosphate, acetate,fumarate, maleate, citrate, lactate, tartrate, oxalate, or similarpharmaceutically-acceptable inorganic or organic acid addition salt.

The invention also relates to a method of preparing the above mentionedcompounds. This method comprises

a) reacting a reactive derivative of a compound selected from the groupconsisting of ##STR11## wherein R¹, R⁴ and ##STR12## have the meaningsdefined above, with a compound having the formula III

    R'--C(═NOH)NH.sub.2                                    (III)

wherein R' has the meaning defined above to form a compound of thegeneral formula I, wherein R³ is ##STR13## wherein R' has the meaningdefined above, or

b) reacting a compound selected from the group consisting of ##STR14##wherein R¹, R⁴ and ##STR15## have the meanings defined above, with NH₂OH, and reacting the compound thus formed with R'--COCl or (R'CO)₂ O,wherein R' has the meaning set forth above, to form a compound offormula I, wherein R³ is ##STR16## wherein R' has the meaning definedabove, or

c) reacting a compound selected from the group consisting of ##STR17##wherein R¹, R⁴ and ##STR18## have the meanings defined above, with analkene, alkyne or a equivalent thereof, to form a compound of thegeneral formula I, wherein R³ is ##STR19## wherein R" has the meaningdefined above, or

d) reacting a compound selected from the group consisting of ##STR20##wherein R¹, R⁴ and ##STR21## have the meanings defined above, with acompound having the formula VII

    NH.sub.2 --O--R'"                                          (VII)

wherein R'" has the meaning set forth above, to form a compound of thegeneral formula I, wherein R³ is

    --CH═N--O--R'"

wherein R'" as the meaning defined above.

e) reacting a compound selected from the group consisting of ##STR22##wherein R¹, R⁴ and ##STR23## have the meanings defined above, with acompound having the formula ##STR24## wherein R'" has the meaning setforth above to form a compound of the general formula I wherein R³ is##STR25## wherein R'" has the meaning defined above.

f) reacting pyridine-3-carbaldehyde with a compound having the formula##STR26## wherein R'" has the meaning set forth above, followed byreaction with R¹ -hal wherein R¹ has the meaning defined above, andreacting the compound thus formed with NaBH₄ to form a compound of thegeneral formula ##STR27##

g) reacting 3-acetylpyridine with a compound having the formula##STR28## wherein R" has the meaning set forth above followed byreaction with NH₂ --OSO₃ H and R¹ -hal wherein R¹ has the meaningdefined above, and reacting the compound thus formed with NaBH₄ to forma compound of the general formula ##STR29##

h) reacting 3-ethynylpyridine with a compound having the formula

    R"CN.sup.+ O.sup.-

wherein R" has the meaning set forth above followed by reaction with R¹-hal wherein R¹ has the meaning defined above, and reacting the compoundthus formed with NaBH₄ to form a compound of the general formula##STR30##

*****

The pharmacological properties of the compounds of the invention can beillustrated by determining their capability to inhibit the specificbinding of ³ H-QNB (³ H-quinuclidinyl benzilate) by 50%. The inhibitoryeffect of a substance on ³ H-QNB binding to brain membranes reflects theaffinity of the substance for muscarinic acetylcholine receptors.(Yamamura, H. I. and Snyder, S. H., Proc. Natl. Acad. Sci. 71,1725-29(1979). The test is carryed out as follows:

Fresh whole forebrain from male Wistar rats (200-250 g) is homogenizedby an Ultra-Turrax homogenizer (5-10 s) in volumes of 0.32M sucrose. Thehomogenate is centrifuged at 4,300×g for 5 min. The pellet is discardedand the supernatant centrifuged at 40,000×g for 15 min. The final pelletis rehomogenized in 50 mM KH₂ PO₄, pH 7.1 (1000 ml per g of originaltissue) and this crude membrane preparation is used for binding assays.To 2.5 ml of tissue suspension is added 25 μl of test solution* and 25μl ³ H-QNB (1 nM final concentration). Samples are thoroughly mixed andincubated at 37° C. for 20 min. after incubation, samples are poureddirectly onto GF/C glass fiber filters under suction and immediatelywashed 2 times with 10 ml of buffer at 0° C. Non-specific binding isdetermined in dublicate using atropin (1 μg/ml, final concentration) asthe test substance. The amounts of radioactivity on the filters aredetermined by conventional liquid scintilation counting. Specificbinding is total binding minus non-specific binding.

* Test compound is dissolved in 10 ml 96% ethanol (if necessary,acidified by 25 μl 1N HCl and heated on a steambath for less than 5minutes) at a concentration of 0.22 mg/ml. Three dilutions are made in48% ethanol (1.1 μg/ml, 11 μg/ml and 110 μg/ml). Concentrations of 10,100 and 1000 ng/ml (final concentration) are added to duplicate assays.25-75% inhibition of specific binding must be obtained, beforecalculation of IC₅₀.

The test value will be given as IC₅₀ (the concentration/μg/ml) of thetest substance which inhibits the specific binding of ³ H-QNB by 50%).##EQU1## where C_(o) is specific binding in control assays and C_(x) isthe specific binding in the test assay (the calculation assumes normalmass-action interaction).

The compound of the invention, together with a conventional adjuvant,carrier, or diluent, and if desired in the form of apharmaceutically-acceptable acid addition salt thereof, may be placedinto the form of pharmaceutical compositions and unit dosages thereof,and in such form may be employed as solids, such as tablets or filledcapsules, or liquids, such as solutions, suspensions, emulsions,elixirs, or capsules filled with the same, all for oral use, in the formof suppositories for rectal administration; or in the form of sterileinjectable solutions for parenteral (including subcutaneous) use. Suchpharmaceutical compositions and unit dosage forms thereof may compriseconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and such unit dosage formsmay contain any suitable effective muscarinic cholinergic agonisticamount of the active ingredient commensurate with the intended dailydosage range to be employed. Tablets containing ten (10) milligrams ofthe active ingredient or, more broadly, one (1) to hundred (100)milligrams, per tablet, are accordingly suitable representative unitdosage forms.

The compounds of this invention can thus be used for the formulation ofpharmaceutical preparations, e.g. for oral and parenteral administrationto mammals including humans, in accordance with conventional methods ofgalenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral or enteralapplication which do not deleteriously react with the active compounds.

Examples of such carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or coloring substances and the like, which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Ampoules are convenient unit dosage forms.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like, the carrier preferably being lactose and/or cornstarch and/or potato starch, are particularly suitable for oralapplication. A syrup, elixir of the like can be used in cases where asweetened vehicle can be employed.

Generally, the compounds of this invention are dispensed in unit formcomprising 1-100 mg in a pharmaceutically acceptable carrier per unitdosage.

The dosage of the compounds according to this invention is 1-100 mg/daypreferably 10-70 mg/day when administered to patients, e.g. humans, as adrug.

A typical tablet which may be prepared by conventional tablettingtechniques contains:

    ______________________________________                                        Active compound     5.0    mg                                                 Lactosum            67.8   mg Ph.Eur.                                         Avicel ®        31.4   mg                                                 Amberlite ® IRP 88                                                                            1.0    mg                                                 Magnesii stearas    0.25   mg Ph.Eur.                                         ______________________________________                                    

Due to the high muscarinic cholinergic receptor agonistic activity, thecompounds of the invention are extremely useful in the treatmentsymptoms related to a reduction of the cognitive functions of the brainof mammals , when administered in an amount effective for stimulatingthe cognitive functions of the forebrain and hippocampus. The importantstimulating activity of the compounds of the invention includes bothactivity against the pathophysiological disease, Alzheimer's disease aswell as against normal degeneration of brain function. The compounds ofthe invention may accordingly be administered to a subject, e.g., aliving animal body, including a human, in need of stimulation of thecognitive functions of the forebrain and hippocampus, and if desired inthe form of a pharmaceutically-acceptable acid addition salt thereof(such as the hydrobromide, hydrochloride, or sulfate, in any eventprepared in the usual or conventional manner, e.g., evaporation todryness of the free base in solution together with the acid), ordinarilyconcurrently, simultaneously, or together with apharmaceutically-acceptable carrier or diluent, especially andpreferably in the form of a pharmaceutical composition thereof, whetherby oral, rectal, or parenteral (including subcutaneous) route, in aneffective forebrain and hippocampus stimulating amount, and in any eventan amount which is effective for improving the cognitive function ofmammals due to their muscarinic cholinergic receptor agonistic activity.Suitable dosage ranges are 1-100 milligrams daily, 10-100 milligramsdaily, and especially 30-70 milligrams daily, depending as usual uponthe exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and the preferenceand experience of the physician or veterinarian in charge.

The invention will now be described in further detail with reference tothe following examples:

EXAMPLE 12-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate

Sodium (56.6 mg, 2.46 mmol) was dissolved in absolute ethanol (12 ml).Molecular sieves (Type 4A, 1.3 g) and cyclopropancarboxamide oxime (330mg, 3.30 mmol) were added and the resulting mixture vigorously stirredfor 15 min. before addition of cocaine hydrochloride (280 mg, 0.82mmol). The reaction mixture was heated at 80° for 20 hours. The solutionwas then filtered from the molecular sieves and the solvent was removedin vacuo. Ether (75 ml) was added to the residue followed by water (20ml) and the organic phase was separated. The aqueous phase was extractedwith ether (2-75 ml), and the combined ether phases were dried (MgSO₄,filtered and evaporated.

The title compound was isolated as the oxalate, which was recrystallizedfrom absolute ethanol/ether. M.p. 117° C.

In exactly the same manner the following compound was made:

2-(3-n-butyl-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate. M.p. 174° C.

EXAMPLE 22-(3-Isopropyl-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate

Sodium (303 mg, 13.2 mmol) was dissolved in absolute ethanol (60 ml).Molecular sieves (Type 4A, 7 g) and isopropancarboxamide oxime (2.64 g,26.4 mmol) were added and the resulting mixture vigorously stirred for15 min. before addition of cocaine (2.0 g, 6.6 mmol). The reactionmixture was heated at 80° for 24 h and at room temperature for 24 h. Thesolution was then filtered from the molecular sieves and the solvent wasremoved in vacuo. Ether (250 ml) was added to the residue followed bywater (100 ml) and the organic phase was separated. The aqueous phasewas extracted with ether (2×250 ml), and the combined ether phases weredried (MgSO₄), filtered and evaporated to give an oil, which waschromatographed on silica gel eluting with ethylacetate and ethanol. Thetitle compound was isolated as the oxalate, which was recrystallizedfrom absolute ethanol/ether. M.p. 162° C.

In exactly the same manner the following compounds were made:

2-(3-Methoxymethyl-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate M.p. 139° C.

2-(3-(2-Methoxyethyl)-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate M.p. 165° C.

EXAMPLE 32-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-2-enehydrochloride

2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-methyl-8-azabicyclo[3.2.1]oct-2-ene(525 mg, 2.3 mmol) was dissolved in dry dichlorethane (10 ml). Thesolution was cooled on ice and 1-chloroethyl chloroformate (370 μl, 3.4mmol was added). The reaction mixture was heated under reflux for 1.5 hand the solvent evaporated. Methanol (20 ml) was added and the mixtureheated under reflux for further 1.5 h. The mixture was treated withcharcoal, filtered and concentrated in vacuo.

The product was recrystallized from absolute ethanol/ether. M.p. 86° C.

In exactly the same manner the following compounds were made:

2-(3-(2-Methoxyethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-2-enehydrochloride, M.p. 62 ° C.

2-(3-Isopropyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-2-eneoxalate, M.p. 168° C.

EXAMPLE 43-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-didehydroquinuclidine oxalate

Sodium (181 mg, 7.86 mmol) was dissolved in absolute ethanol (45 ml).Molecular sieves (Type 4A, 5 g) and cyclopropancarboxamide oxime (786mg, 7.86 mmol) were added and the resulting mixture vigorously stirredfor 15 min. before addition of3-methoxycarbonyl-2,3-didehydroquinuclidine, HCl; prepared as describedby Grob et al. in Helv. Chim. Acta. (1954), 37, 1689. The reactionmixture was heated at 80° C. for 18 h. The solution was then filteredfrom the molecular sieves and the solvent was removed in vacuo. Ether(50 ml) was added to the residue followed by water (25 ml) and theorganic phase was separated. The aqueous phase was extracted with ether(3×50 ml), and the combined ether phases were dried (Na₂ SO₄) andevaporated to give an oil. This material in dichloromethane (50 ml) wastreated for 15 min. at 20° C. with potassium t-butoxide (3 g, 26.79mmol). After filtration, the material isolated from the filtrate waschromatographed on silica gel eluting with ethylacetate-methanol(3.2:1). The title compound was isolated as the oxalate salt. M.p.189.0° C.

EXAMPLE 5 3-(3-Isopropyl-1,2,4-oxadiazol-5-yl)-quinuclidine oxalate

Sodium (224 mg, 9.74 mmol) was dissolved in absolute ethanol (45 ml).Molecular sieves (Type 4A, 5 g) and isopropancarboxamide oxime (993 mg,9.74 mmol) were added and the resulting mixture vigorously stirred for15 min. before addition of 3-methoxycarbonyl-quinuclidine HCl preparedas described by Grob et al. in Helv. Chim. Acta. (1954), 37, 1689. Thereaction mixture was heated at 80° C. for 18 h. The solution was thenfiltered from the molecular sieves and the solvent was removed in vacuo.Ether (50 ml) was added to the residue followed by water (25 ml) and theorganic phase was separated. The aqueous phase was extracated with ether(3×50 ml), and the combined ether phases were dried (Na₂ SO₄) andevaporated to afford the title oxadiazole as an oil. The product wasfurther purified as the oxalate salt. M.p. 118°-119°.

In exactly the same manner the following compounds were prepared:

3-(3-butyl-1,2,4-oxadiazol-5-yl)-quinuclidine oxalate, M.p. 122°-124° C.

3-(3-methoxymethyl-1,2,4-oxadiazol-5-yl)-quinuclidine oxalate, M.p.107°-108° C.

3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-quinuclidine oxalate, M.p.156°-157° C.

EXAMPLE 6 1-Benzoyl-4-chloro-3-formyl-1,2,5,6-tetrahydropyridine oxime

To a solution of 14.6 g (200 mmol) dimethylformamide in 50 mlmethylenechloride at 0° C. was added 24.52 g (160 mmol) phosphorusoxychloride at such a rate that the temperature did not exceed 10° C.After addition the reaction mixture was stirred for 1 h at roomtemperature. The mixture was again cooled to 0° C. and 20.32 g (100mmol) 1-benzoyl-4-piperidone in 30 ml methylenechloride was addeddropwise. After addition (30 min.), the reaction mixture was stirred atroom temperature for 2 h whereupon, 150 g crushed ice was added and themixture stirred until the ice had dissolved. Solid sodium acetate (70 g)was added, and the mixture stirred for 15 min. The methylenechloridefraction was isolated and the aqueous portion was extracted with 2×50 mlmethylenechloride. The combined methylenechloride extracts were pouredin 100 ml of a saturated sodium bicarbonate solution, and the mixturestirred vigorously for 15 min. The methylenechloride fraction was thenisolated, washed with water, dried over magnesium sulfate andconcentrated to a volume of 50 ml. To this solution was added 100 mlethanol, hydroxylamine hydrochloride (6.65 g, 100 mmol) and 15 mltriethylamine. The reaction mixture was stirred overnight, 200 ml waterwas added and the methylenechloride fraction isolated. The aqueousportion was extracted with 2×50 ml methylenechloride. The combinedmethylenechloride extracts were dried over magnesiumsulfate, andconcentrated in vacuo. To the remaining oil was added 50 ml ethanol andthe title compound separated out. Yield: 10.5 g. M.p. 175°-176° C.

In exactly the same manner the following compounds were prepared:

1-Methyl-4-chloro-3-formyl-1,2,5,6-tetrahydropyridine oxime from1-methyl-4-piperidone and hydroxylamine. M.p. 172°-73° C.

1-Benzyl-4-chloro-3-formyl-1,2,5,6-tetradydropyridine oxime from1-benzyl-4-piperidone and hydroxylamine M.p. 148°-151° C.

1-Methyl-4-chloro-3-methoxyiminomethyl-1,2,5,6-tetrahydropyridine from1-methyl-4-piperidone and O-methylhydroxylamine. M.p. 185°-187° C. asoxalate.

8-Ethoxycarbonyl-3-chloro-2-formyl-8-azabicyclo[3.2.1]oct-2-ene oximefrom N-(ethoxycarbonyl)nortropan-3-one (G. L. Grunewald et.al. J. Med.Chem. 1988, 31, 433-44). Oil.

EXAMPLE 71-Benzoyl-4-chloro-3-(5-methoxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine

To a solution of 1-benzoyl-4-chloro-3-formyl-1,2,5,6-tetrahydropyridineoxime (5.3 g, 20 mmol) in 100 ml dry dimethylformamide was addedN-bromosuccinimide (4.5 g, 25 mmol) dissolved in 20 ml drydimethylformamide. The reaction mixture was stirred at room temperaturefor 1 h. Now methylpropargylether (1.5 ml, 25 mmol) and 2 mltriethylamine was added and the reaction mixture stirred at roomtemperature overnight. 200 ml water was added and the aqueous phaseextracted with 3×50 ml ether. The combined ether extracts were washedwith 2×50 ml water, dried over magnesiumsulfate and concentrated invacuo. The compound was finally purified by column chromatography withmethylenechloride/ethylacetate 4:1 as eluent. Yield: 3.5 g. M.p.60.5°-62° C.

In exactly the same manner the following compounds were prepared

1-Benzoyl-4-chloro-3-(5-butyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine

1-Benzoyl-4-chloro-3-(5-hydroxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine

1-Benzoyl-4-chloro-3-(5-dimethylaminomethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine

1-Benzoyl-4-chloro-3-(5-ethoxy-4,5-dihydro-3-isoxazolyl)-1,2,5,6-tetrahydropyridine

8-Ethoxycarbonyl-3-chloro-2-(5-butyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene

8-Ethoxycarbonyl-3-chloro-2-(5-methoxymethyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene

8-Ethoxycarbonyl-3-chloro-2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oxt-2-ene

1-Benzoyl-4-chloro-3-(5-methyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine

To a solution of 1-benzoyl-4-chloro-3-formyl-1,2,5,6-tetrahydropyridineoxime (5,3 g, 20 mmol) in 100 ml dry dimethylformamide was addedN-bromosuccinimide (4.5 g, 25 mmol) dissolved in 20 ml drydimethylformamide. The reaction mixture was stirred at room temperaturefor 1 h. Now 2-bromopropene (2.2 ml, 25 mmol) and 4 ml triethylaminewere added and the reaction mixture stirred at room temperature for 48h. The compound was purified as described for1-Benzoyl-4-chloro-3-(5-methoxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine.Yield: 3.1 g. M.p. 86°-87° C.

In exactly the same manner the following compound was prepared

8-Ethoxycarbonyl-3-chloro-2-(5-methyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene

EXAMPLE 84-Chloro-3-(5-methoxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridineoxalate

A suspension of 1.65 g (5 mmol) of1-benzoyl-4-chloro-3-(5-methoxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridinein 30 ml 6M hydrochloric acid solution was heated at reflux for 5 h.After cooling to room temperature 30 ml water was added and the aqueousphase extracted with 2×30 ml ether. The aqueous phase was made stronglyalkaline with solid potassiumcarbonate and extracted with 2×30 ml ether.The combined ether extracts were dried over magnesiumsulfate andconcentrated in vacuo. The remaining oil was dissolved in 10 ml acetone,and the title compound was precipitated with a 1M oxalic acid acetonesolution. The compound was filtered and dried. Yield: 0.65 g. M.p.155°-156° C.

In exactly the same manner the following compounds were prepared

4-Chloro-3-(5-methyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine oxalatestarting from1-benzoyl-4-chloro-3-(5-methyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine.M.p. 180°-181° C.

4-Chloro-3-(5-butyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine oxalatestarting from1-benzoyl-4-chloro-3-(5-butyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine.M.p. 164°-165° C.

4-Chloro-3-(5-hydroxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridineoxalate starting from1-benzoyl-4-chloro-3-(5-hydroxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine.M.p. 167°-169° C.

4-Chloro-3-(5-dimethylaminomethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridineoxalate starting from1-benzoyl-4-chloro-3-(5-dimethylaminomethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine.M.p. 226°-29° C.

4-Chloro-3-(3-isoxazolyl)-1,2,5,6-tetrahydropyridine oxalate startingfrom1-benzoyl-4-chloro-3-(5-ethoxy-4,5-dihydro-3-isoxazolyl)-1,2,5,6-tetrahydropyridine.M.p. 195°-196° C.

EXAMPLE 9 3-(5-Methoxymethyl-3-isoxazolyl)-1 2 5.6-tetrahydropyridineoxalate

1-Benzoyl-4-chloro-3-(5-methoxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine(0.8 g, 2.5 mmol) was dissolved in 50 ml ethanol. To this solution wasadded a suspension of palladium-on-charcoal (5%, 0.5 g) in 10 ml ethanoland 2 ml triethylamine. The mixture was reduced with hydrogen atatmospheric pressure until exactly 1.2 equivalent of hydrogen wasconsumed. The catalyst was filtered off and the solution concentrated invacuo. The remaining oil was suspended in 20 ml 6M hydrochloric acidsolution and heated at reflux for 5 h. After cooling 20 ml water wasadded and the aqueous solution was extracted with 2×20 ml ether. Theaqueous solution was made strongly alkaline with solid potassiumcarbonate and extracted with 3×20 ml methylenechloride. The combinedmethylenechloride extracts were dried over magnesiumsulfate andconcentrated in vacuo. The remaining oil was dissolved in 10 ml acetone,and the title compound was precipitated with a 1M oxalic acid acetonesolution. The compound was filtered and dried. Yield: 0.2 g. M.p.152°-153° C.

In exactly the same manner the following compounds were prepared:

3-(5-methyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine oxalate startingfrom1-benzoyl-4-chloro-3-(5-methyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine.M.p. 176°-177° C.

3-(5-Butyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine oxalate startingfrom1-benzoyl-4-chloro-3-(5-butyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine.M.p. 188°-91° C.

EXAMPLE 10 3-(5-Propyl-1,2,4-oxadiazol-3-yl)-2,3-didehydroquinuclidineoxalate

To a solution of sodium (575 mg, 25 mmol) in methanol (20 ml) was addeda solution of hydroxylamine hydrochloride (1.55 g, 22 mmol) in methanol(20 ml). The mixture was stirred for 30 min, and filtrated. To thefiltrate a solution of 3-cyano-2,3-didehydroquinuclidine (Helv. Chem.Acta 40, 2170 (1957)) (1.2 g, 9 mmol) in methanol (5 ml) was added andthe reaction mixture was stirred at room temperature for 48 h. Afterevaporation the residue was suspended in absolute ethanol (25 ml),filtered and evaporated to give the 2,3-didehydroquinuclidineamideoxime. The amide oxime (700 mg) was dissolved in butyric anhydride andstirred at 100° C. for 16 h. After evaporation the residue was dissolvedin a saturated potassium carbonate solution (10 ml) and extracted withether (3×75 ml). The combined organic phases were dried and evaporated.The residue was purified (column chromatography with1,2-dichloroethane-methanol (9:1) as eluent). Crystallization as theoxalate salt from acetone gave the title compound in a 300 mg yield.M.p. 155°-157° C.

3-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-didehydroquinuclidine oxalate

This compound was synthesized as described above usingcyclopropanecarboxylic acid chloride followed by cyclization inrefluxing toluene instead of butyric anhydride. M.p. 170-°172° C.

8-Methyl-2-(5-propyl-1,2,4-oxadiazol-3-yl)-8-azabicyclo[3.2.1]oct-2-eneoxalate

This compound was synthesized as described above starting from2-cyano-8-methyl-8-azabicyclo[3.2.1]oct-2-ene [J. C. S. Perkin I, 1981,1346°-1351]. M.p. 99°-101° C.

EXAMPLE 11 3-(5-Oxazolyl)-1,2,5,6-tetrahydro-1-methylpyridine oxalate

To a solution of 1-methyl-3-formyl-1,2,5,6-tetrahydropyridinehydrochloride (Mannich Berichte 75, 1480-83, 1942) 1.60 g, 10 mmol) in20 ml methanol powdered potassium carbonate (3 g) was added. Thentosylmethylisocyanide (1.95 g, 10 mmol) was added and the reactionmixture stirred at room temperature for 2 h. Upon evaporation in vacuo,water (30 ml) was added to the residue, and the solution was extractedwith methylenechloride 3×20 ml. The combined methylenechloride extractswere dried over magnesiumsulfate and evaporated in vacuo. The crudecompound was purified by column chromatography with acetone as eluent.The title compound was precipitated with a 1M oxalic acid acetonesolution, filtered and dried. M.p. 169°-170° C.

1-Methyl-3-(4-propyl-5-oxazolyl)-1,2,5,6-tetrahydropyridine oxalate

A mixture of 1.07 g (10 mmol) pyridin-3-carbaldehyde 2.61 g (11 mmol)1-tosyl-1-isocyanobutane and powdered potassium carbonate in methanol(50 ml) was stirred for 12 h at room temperature. The reaction mixturewas concentrated in vacuo and water (100 ml) was added. The watersuspension was extracted with 3×30 ml ethylacetate. The organic phasewas dried over magnesiumsulfate and concentrated in vacuo. The residuewas dissolved in 50 ml acetone and 3.12 g (22 mmol) methyliodide wasadded. The reaction mixture was stirred overnight at room temperature,concentrated in vacuo and titurated with ethylacetate. The precipitatedcrystals were dissolved in ethanol (50 ml) and treated with 1.06 g (28mmol) sodiumborohydride. The mixture was concentrated in vacuo and water(100 ml) was added. The water suspension was extracted with 3×30 mlmethylenchloride. The organic phase was dried over magnesium sulfate andconcentrated in vacuo. The compound was purified by columnchromatographay with ethylacetate/methanol (9:1) as eluent.Crystallization as the oxalate salt from acetone gave the title compoundin a 940 mg yield. M.p. 100°-101° C.

EXAMPLE 12 3-(Cyclopropylmethoxyiminomethyl)-1 25.6-tetrahydro-1-methylpyridine oxalate

To a solution of 1-methyl-3-formyl-1,2,5,6-tetrahydropyridinehydrochloride (Mannich Berichte 75, 1480-83, 1942) (1.60 g, 10 mmol) in20 ml ethanol cyclopropylmethoxyamine hydrochloride (1.24 g, 10 mmol)and triethylamine (3 ml) were added. The reaction mixture was stirred atroom temperature for 1 h, then evaporated in vacuo. 30 ml sodiumhydroxide solution (0.5M) was added to the residue, and the solution wasextracted with methylenechloride (3×20 ml). The combinedmethylenechloride extracts were dried and evaporated in vacuo. Theresidue was dissolved in acetone and the title compound was precipitatedwith a 1M oxalic acid acetone solution. The compound was filtered anddried. M.p. 143°-144° C.

EXAMPLE 13 3-Chloro-2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate

To a dimethylformamide (4.5 ml, 60 mmol) at 0° C. was added phosphorousoxychloride (3 ml, 30 mmol). Tropinone (2 g, 13 mmol) was added, and thereaction mixture heated to 70° C. for 1/2 h After cooling, crushed icewas added and then solid potassium carbonate until alkaline reaction.The water solution was extracted with ether (3×30 ml). The etherextracts were dried and evaporated. The crude compound was purified bycolumn chromatography with acetone as eluent. The title compound wasprecipitated with a 1M oxalic acid acetone solution, filtered and dried.M.p. 136°-137° C. decomposes.

EXAMPLE 143-Chloro-2-(cyclopropylmethoxyiminomethyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate

To a solution of 3-chloro-2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate (0.55 g, 2 mmol) in 20 ml ethanol cyclopropylmethoxyaminehydrochloride (0.25 g, 2 mmol) and triethylamine (1 ml) was added. Thereaction mixture was stirred at room temperature for 1 h, thenevaporated in vacuo. 20 ml sodiumhydroxide solution (0.5M) was added tot he residue, and the solution was extracted with methylenechloride(3×15 ml). The combined methylenechloride extracts were dried andevaporated in vacuo. The residue was dissolved in acetone (10 ml) andthe title compound was precipitated with a 1M oxalic acid acetonesolution. The compound was filtered and dried M.p 170°-171° C.

In exactly the same manner the following compound was prepared:

3-Chloro-2-(methoxyiminomethyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate from 3-chloro-2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate and methoxyamine hydrochloride, M.p. 180°-185° C.

EXAMPLE 15 3-Chloro-8-methyl-2-(5-oxazolyl)-8-azabicyclo[3.2.1]oct-2-eneoxalate

To a solution of 3-chloro-2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate (0.55 g, 2 mmol) in 20 ml methanol powdered potassium carbonate(1.5 g) and tosylmethylisocyanide (0.4 g, 2 mmol) was added. Thereaction mixture was stirred at room temperature for 2 h. Uponevaporation in vacuo water (30 ml) was added to the residue and thewater solution extracted with methylenechloride (3×20 ml). The combinedmethylenechloride extracts were dried and evaporated in vacuo. Theresidue was dissolved in ethanol, and the title compound precipitatedwith a 1M oxalic acid ether solution. The compound was filtered anddried. M.p. 69°-71° C. decomposes.

EXAMPLE 16 2-Methoxyiminomethyl-8-methyl-8-azabicyclo[3.2.1]oct-2-eneoxalate

To a solution of 2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (T.Bacesov and M. Shives, J. Am. Chem. Soc., 107, 7524-33, 1985) (0.3 g, 2mmol) in 20 ml ethanol methoxyamine hydrochloride (0.17 g, 2 mmol) andtriethylamine 0.5 ml was added. The reaction mixture was stirred at roomtemperature for 1 h, then evaporated in vacuo. Sodiumhydroxide solution(20 ml, 0.5 mmol) was added to the residue and the solution wasextracted with methylenechloride (3×15 ml). The combinedmethylenechloride extracts were dried and evaporated in vacuo. Theresidue was dissolved in acetone (5 ml) and the title compound wasprecipitated with a 1M oxalic acid acetone solution. The compound wasfiltered and dried. M.p. 129°-130° C.

In exactly the same manner the following compound was prepared:

2-Ethoxyiminomethyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene oxalate from2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene and ethoxyaminehydrochloride. M.p. 127°-128° C.

EXAMPLE 173-(3-Cyclobutyl-1,2,4-oxadiazol-5-yl)-1-methyl-1,2,5,6-tetrahydropyridineoxalate

To a solution of sodium ethoxide (prepared from sodium (34 mg, 1.48mmol), destilled ethanol (20 ml) and molecular sieves (4 g) was addedcyclobutancarboxamide oxime (169 mg, 1.48 mmol). The mixture was stirredat room temperature for 10 min. and arecoline, hydrobromide (175 mg,0.74 mmol) was added. The reaction mixture was stirred at 80° C. for 18h, filtered and evaporated. Water (10 ml) was added to the residue, andthe solution was extracted with ether (3×30 ml). The combined etherphases were dried and evaporated to give the crude product as an oil.Crystallization as the oxalate salt from absolute ethanol gave the titlecompound in a yield of 60 mg. M.p. 148°-149° C.

In exactly the same manner the following compounds were prepared:

3-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)-1-methyl-1,2,5,6-tetrahydropyridineoxalate. M.p. 132°-133° C.

3-(3-(2-methoxyethyl)-1,2,4-oxadiazol-5-yl)-1-methyl-1,2,5,6-tetrahydropyridineoxalate. M.p. 140°-141° C.

3-(3-(2-ethoxyethyl)-1,2,4-oxadiazol-5-yl)-1-methyl-1,2,5,6-tetrahydropyridineoxalate. M.p. 143°-144° C.

3-(3-(2-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-1-methyl-1,2,5,6-tetrahydropyridineoxalate. M.p. 76°-77° C.

Using norarecoline instead of arecoline the following compounds weremade in exactly the same manner as described above:

3-(3-cyclobutyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyridineoxalate. M.p. 202°-205° C.

3-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)-1,2,5,6-tetrahydropyridineoxalate. M.p. 152°-158° C.

EXAMPLE 18 3-(5-Isoxazolyl)-1-methyl-1,2,5,6-tetrahydropyridine oxalate

A mixture of 12.1 g (0.1 mol) 3-acetyl pyridine and 15 g (0.11 mol)dimethyl formamide dimethylacetale was heated at 90° C. for 2 h. Uponconcentration in vacuo the product was titrated with ethylether andfiltrated. The compound was dissolved in 50 ml methanol and 11.5 g (0.1mol) hydroxylamine-O-sulfonic acid dissolved in 50 ml MeOH was added.The reaction mixture was stirred at room temperature for 2 h,concentrated in vacuo and poured on water (150 ml). The solution wasmade alkaline with solid potassium carbonate and extracted with 4×40 mlmethylenchloride. The organic phase was dried over magnesium sulfate andconcentrated in vacuo. The crude product was purified by columnchromatography giving 1.5 g 3-(5-isoxazolyl)-pyridine, which wasdissolved in 20 ml acetone. 3 ml methyliodide was added to the solution,and the reaction mixture was stirred at room temperature for 24 h. Theprecipitated compound was filtered and dissolved in 30 ml methanol. Tothis solution sodiumborohydride (600 mg) was added in small portions.The reaction mixture was concentrated in vacuo and water (100 ml) wasadded. The water solution was extracted with 3×30 ml methylenchloride.The organic phase was dried over magnesiumsulfate and concentrated invacuo. Crystallization as the oxalate salt from acetone gave the titlecompound in a 1.1 g yield. M.p. 164°-165° C.

3-(3-Methyl-5-isoxazolyl)-1,2,5,6-tetrahydropyridine oxalate

This compound was prepared as described above starting from3-acetylpyridine and dimethylacetamide dimethylacetale. M.p. 167°-169°C.

3-(3-Ethyl-5-isoxazolyl)-1-methyl-1,2,5,6-tetrahydropyridine oxalate

0.45 g (5 mmole) nitropropane and 5 ml 1N (5 mmole) sodiummethoxide wasdissolved in dry dimethylacetamide (25 ml). To this solution 0.39 g (5mmole) acetylchloride and 0.51 g (5 mmole) 2-ethynylpyridine was added.The reaction mixture was stirred overnight at room temperature. Water(150 ml) was added, and the solution extracted with 3×30 mlethylacetate. The organic phase was dried over magnesiumsulphate andconcentrated in vacuo giving 3-(3-ethyl-5-isoxazolyl)pyridine in a 500mg yield. This compound was quartarnized with methyliodide and reducedwith sodiumborohydride as described above giving the title compound in a170 mg yield. M.p. 169°-170° C.

EXAMPLE 193-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-1,4-dimethyl-1,2,5,6-tetrahydropyridineoxalate

Sodium (54.4 mg, 2.37 mmol) was dissolved in absolute ethanol (10 ml).Molecular sieves (Type 4 Å, 1 g) and cyclopropanylcarboxamide oxime (236mg, 2.37 mmol) were added and the resulting mixture vigorously stirredfor 15 min. before addition of1,4-dimethyl-3-methoxycarbonyl-1,2,5,6-tetrahydropyridine oxalate (200mg, 1.18 mmol). The reaction mixture was heated at 80° C. for 18 h. Thesolution was then filtered from the molecular sieves and the solvent wasremoved in vacuo. Ether (40 ml) was added to the residue followed bywater (15 ml) and the organic phase was separated. The aqueous phase wasextracted with ether (3×40 ml), and the combined ether phases were dried(Na₂ SO₄) and evaporated to afford the title oxadiazole as an oil. Theproduct was further purified as the oxalate salt. M.p. 152°-153° C.

In exactly the same manner the following compound was prepared:

3-(3-Butyl-1,2,4-oxadiazol-5-yl)-1,4-dimethyl-1,2,5,6-tetrahydropyridineoxalate. M.p. 147°-148° C.

EXAMPLE 203-Chloro-2-(5-butyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene oxalate

To a solution of 1.0 g (3 mmol) of8-ethoxycarbonyl-3-chloro-2-(5-butyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-enein dry toluene (20 ml), 2 g (15 mmol) aluminiumtrichloride was added.The reaction mixture was heated at 70° C. for 15 min., then cooled andpoured on ice water (100 ml). The phases were separated and the waterphase extracted with 2×20 ml ethylether. The water phase was madealkaline With a sodiumhydroxide solution (2 N), and extracted with 3×30ml methylenchloride. The organic phase was dried over magnesiumsulphateand concentrated in vacuo. Crystallization as the oxalate salt fromacetone gave the title compound in a 450 mg yield. M.p. 112°-114° C.

In exactly the same manner the following compounds were prepared:

3-Chloro-2-(5-methoxymethyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-eneoxalate. M.p. 153°-154° C.

3-Chloro-2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene oxalate.M.p. 135°-136° C.

3-Chloro-2-(5-methyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene oxalate.M.p. 136°-137° C.

2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene oxalate. M.p.163°-164° C.

EXAMPLE 218-Ethoxycarbonyl-2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene

1.3 g (3.6 mmol)8-ethoxycarbonyl-3-chloro-2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-enewas dissolved in 30 ml ethanol. 300 mg Pd/C 5%, triethylamine (7 ml) andformic acid (3 ml) was added and the reaction mixture heated at refluxfor 4 h. The mixture was concentrated in vacuo, water (50 ml) was addedand the solution extracted with ethylether 3×20 ml. The organic phasewas dried over magnesiumsulphate and concentrated in vacuo. The crudeproduct was purified by column chromatography withmethylenchloride/ethylacetate (9:1) as eluent. Yield 600 mg oil.

EXAMPLE 224-Chloro-3-(5-methoxymethyl-3-isoxazolyl)-1-methyl-1,2,5,6-tetrahydropyridineoxalate

To a mixture of formic acid (5 ml) and formaldehyde 37% (10 ml) 1.6 g (5mmole)4-chloro-3-(5-methoxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridineoxalate was added. The reaction mixture was heated at reflux for 1 h.After cooling the reaction mixture was poured on water (50 ml) and madealkaline with solid potassiumcarbonate. The water phase was extractedwith 3×30 ml methylenchloride. The organic phases were dried overmagnesiumsulphate and concentrated in vacuo. Crystallization as theoxalate salt from acetone gave the title compound in a 1.25 g yield.M.p. 171°-172° C.

In exactly the same manner the following compounds were prepared:

3-Chloro-8-methyl-2-(5-methyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-eneoxalate with3-chloro-2-(5-methyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene oxalateas starting compound. M.p. 149°-150° C.

3-Chloro-8-methyl-2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-eneoxalate with3-chloro-2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene oxalateas starting compound. M.p. 260°-261° C.

We claim:
 1. A compound of formula I ##STR31## wherein p1 R¹ is H orC₁₋₆ -alkyl; R³ is ##STR32## wherein R' is benzyl or methoxybenzyl;R⁴ isH, C₁₋₈ -alkyl or Cl; and ##STR33## or a pharmaceutically acceptablesalt thereof.
 2. The compound according to claim 1, wherein R¹ is H ormethyl and R⁴ is H or methyl.
 3. The compound according to claim 2 whichis3-(3-(2-methoxybenzyl)-1,2,4-oxadiazol-5-yl)-1-methyl-1,2,5,6-tetrahydropyridineor a pharmaceutically acceptable salt thereof.
 4. A compound of formulaII ##STR34## wherein R¹ is H or C₁₋₆ -alkyl;R³ is ##STR35## wherein R'is C₃₋₈ -cycloalkyl, benzyl or methoxybenzyl and R" is H, C₁₋₈ -alkyl,C₁₋₆ -alkoxy, C₁₋₄ -alkoxy-C₁₋₄ -alkyl or phenyl; R⁴ is H, C₁₋₈ -alkylor Cl; and ##STR36## or a pharmaceutically acceptable salt thereof. 5.The compound according to claim 4, wherein R¹ is H or methyl and R⁴ is Hor methyl.
 6. The compound according to claim 5 which is2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-eneor a pharmaceutically acceptable salt thereof.
 7. The compound accordingto claim 5 which is3-chloro-2-(5-butyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene or apharmaceutically acceptable salt thereof.
 8. The compound according toclaim 5 which is3-chloro-2-(5-methoxymethyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-eneor a pharmaceutically acceptable salt thereof.
 9. The compound accordingto claim 5 which is3-chloro-2-(5-methyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-ene or apharmaceutically acceptable salt thereof.
 10. The compound according toclaim 5 which is3-chloro-8-methyl-2-(5-methyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-eneor a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 5 which is2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1oct-2-ene or apharmaceutically acceptable salt thereof.
 12. The compound according toclaim 5 which is3-chloro-2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1oct-2-ene or apharmaceutically acceptable salt thereof.
 13. The compound according toclaim 5 which is 2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1]oct-2-eneor a pharmaceutically acceptable salt thereof.
 14. The compoundaccording to claim 5 which is3-chloro-8-methyl-2-(5-phenyl-3-isoxazolyl)-8-azabicyclo[3.2.1oct-2-eneor a pharmaceutically acceptable salt thereof.
 15. A compound of formulaIII ##STR37## wherein R³ is ##STR38## wherein R' is C₃₋₈ -cycloalkyl,benzyl or methoxybenzyl; and ##STR39## or a pharmaceutically acceptablesalt thereof.
 16. The compound according to claim 15 which is3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-didehydroquinuclidine or apharmaceutically acceptable salt thereof.
 17. The compound according toclaim 15 which is 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-quinuclidine ora pharmaceutically acceptable salt thereof.
 18. The compound accordingto claim 15 which is3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,3-didehydroquinuclidine or apharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition suitable for use in treating Alzheimer's disease, comprisingan effective amount of a compound according to claim 1, 4 or 15 togetherwith a pharmaceutically acceptable carrier or diluent.
 20. Thepharmaceutical composition according to claim 19 in the form of an oraldosage unit containing 1-100 mg of the active compound.
 21. A method fortreating Alzheimer's disease comprising administering to a subject inneed thereof an effective amount of a compound according to claim 1, 4or
 15. 22. A method for treating Alzheimer's disease, comprisingadministering to a subject in need thereof a pharmaceutical compositionaccording to claim 19.